Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine.
Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.
Boutefnouchet
Sabrina
S
Laboratoire de Pharmacognosie de l'Université Paris Descartes, U.M.R./C.NRS No. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
Gaboriaud-Kolar
Nicolas
N
Nguyen
Tuan Minh
TM
Depauw
Sabine
S
David-Cordonnier
Marie-Hélène
MH
Pfeiffer
Bruno
B
Léonce
Stéphane
S
Pierré
Alain
A
Tillequin
François
F
Lallemand
Marie-Christine
MC
Michel
Sylvie
S
D054831:Acridones / Q000737:chemistry*; D000175:Acronine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D054831:Acridones; D001572:Benzofurans; C436732:S 23906-1; D044004:Xanthones; C025543:psorospermin; D000175:Acronine